JPS6013028B2 - Trifluoromethyl-substituted compounds with antidepressant activity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel trifluoromethyl-substituted aralkyl esters of amino acids and processes for their production.

The invention further relates to methods of pharmacological use of said compounds and formulations containing said compounds. The object of the present invention is to provide a compound that has an effect on the central nervous system, particularly antidepressant activity, has reduced side effects, and is more effective than drugs currently used in this field.

Furthermore, it is an object of the invention to provide preparations containing a compound according to the invention as active ingredient.

Still another object of the present invention is to provide a method for treating depression.

The compound currently most widely used to control depression is the formula imipramine (trade name Tofranil).

Although this compound is mood elevating and psychomotor activating, it has several drawbacks. That is, imipramine is anti-parasympathetic and causes anti-parasympathetic symptoms such as lagoon, tremors, diaphoresis, and sweating. At relatively high doses it causes severe cardiac arrhythmias, and at standard doses it induces toxic interactions in patients with heart failure. Furthermore, a drawback of treatment with imipramine is the slow onset of the antidepressant effect, which is only noticed about 3 weeks after treatment. Imipramine is known to influence the actions of transmitters in the central nervous system.

More specifically, imipramine is noradrenaline (N
A) and inhibits the reabsorption mechanism of 5-hydroxytryptamine (5-HT). It is expected that the mood-elevating part of the antidepressant effect is primarily related to the suppression of 5-HT absorption. According to the present invention, certain novel compounds, which can be described as trifluoromethyl-substituted aralkyl esters of amino acids, can be used for the selective inhibition of central nervous system absorption of 5-hydroxytributamine. was discovered.

Furthermore, the cardiotoxicity of the new compound is considerably less than that of imipramine. The novel compounds according to the invention can be represented by the general formula (wherein Ro is trifluoromethyl) and its pharmaceutically acceptable acid addition salts.

The following two compounds may be mentioned as examples of suitable compounds according to the invention.

2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-12-methyl-2-propyl ester 2-aminopropanoic acid 1-(4-trifluoromethylphenyl)-12-methyl-2-propyl ester.

The compounds of the present invention have the general formula (In the formula, Ro is trifluoro.

methyl and X is a halogen such as chlorine or bromine or p-toluenesulfonyloxy) with ammonia. The intermediate of general formula 0 is a novel compound and constitutes yet another aspect of the present invention. This compound converts the alcohol of the general formula (wherein Ro represents the above meaning) into the alcohol of the formula Y-CO-C
It can be produced by reacting with a compound of H(CH3)× (in the formula, x represents the above meaning and Y is bromine or chlorine).

The reaction of the general formula 0 with ammonia is preferably carried out in an inert organic solvent capable of dissolving the reaction components.

Any suitable reaction pressure and reaction temperature can be employed. Preferably the reaction is carried out under atmospheric pressure or superatmospheric pressure.
It is carried out at a temperature of 0° C. to +100° C., preferably 0 to 30 am. The novel compounds of the invention can be used therapeutically as a racemic mixture of the (decade) and (mono)forms obtained in the usual case during synthesis.

Said mixtures can be further divided into the corresponding optically active modifications by methods known per se, and these modifications can likewise be used therapeutically. If desired, said optically active modifications can also be prepared by direct synthetic methods, for example via the optically active compounds of general formula 0 described above. Clinically, the compounds of the invention are usually administered orally, rectally or by injection in the free base or in the form of, for example, the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate salt. , (for formulations comprising a cleansing ingredient in the form of any pharmaceutically acceptable non-toxic acid addition salt, such as enesulfate, tartrate, oxalate, etc., in combination with a pharmaceutically acceptable carrier). administered in the form of

Therefore, regardless of whether the term relating to the novel compound of the present invention is a general expression or a specific expression, for example, in a particular example, the context of the sentence in which the term is used is inconsistent with the broader concept. If not, it is intended to include both the free amine base and the acid addition salt of the free base. The aforementioned carrier can be a solid, semi-solid or liquid diluent or a capsule. Active substance 0.1
Said formulations containing ˜95% by weight constitute yet another aspect of the invention. Usually, the active substance is 0.5 to
2 of the formulation and suitable for oral administration.
~5% by weight. In order to prepare formulations containing the compounds of the invention in dosage unit form for oral application, the selected compounds may be prepared in a solid powder form, e.g. lactose,
Starches such as sugar, callose, sorbitol, mannite, potato starch, corn starch or amylobectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol wax. tablets, etc., and then compressed to form tablets.

If coated tablets are desired, the tablet cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc, titanium dioxide, and the like. Alternatively, the tablets can be coated with a lacquer dissolved in a readily volatile organic solvent or organic solvent mixture. Dyes may be added to the coating in order to easily distinguish between tablets containing different active substances or different amounts of active compound. Soft gelatin capsules consisting of gelatin and, for example, glycerol (to produce sealed pearl-shaped capsules, the active substance can be mixed with vegetable oil).

Hard gelatin capsules contain granules of the active substance such as lactose,
It may be included in combination with a solid powder carrier such as sutucarose, sorbitol, mannite, starch (eg potato starch, corn starch or amylobectin), cellulose derivatives or gelatin. Dosage unit forms for rectal application can be prepared in the form of suppositories consisting of the active substance admixed with neutral fatty bases or gelatin rectal capsules consisting of the active substance admixed with vegetable or paraffin oil.

Liquid preparations for oral application are in the form of syrups or suspensions, for example containing from about 0.2% to about 2% by weight of said active substance, the balance being sugars and ethanol, water, glycerol and propylene glycol. The solution may be a mixture. Optionally, the aforementioned liquid formulations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent. Solutions to be applied parenterally by injection are prepared in the form of an aqueous solution containing a pharmaceutically acceptable water-soluble salt of the active substance, preferably in a concentration of about 0.5% to about 1% by weight. obtain.

These solutions also contain stabilizers and/or buffers and can advantageously be supplied as ampoules in various dosage units. Suitable daily doses of the compounds of the invention in therapeutic treatment are from 100 to 500 g for oral administration and from 20 to 100 g for parenteral administration.

Preferred compounds of the invention have the formula:

Preferably, this compound is prepared and used in the form of its hydrochloride. The following examples illustrate the preparation of compounds according to the invention.

Preparation of 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester Solution of 3-trifluoromethylbenzyl chloride (25.0 m, 0.128 mol) in ether (130 M) Magnesium (3.11 evening, 0.128
mol).

Spontaneous reflux was continued for an additional 30 minutes. The solution was cooled, acetone (7.45 min, 0.128 mol) was added dropwise (8 minutes), and the solution was heated to reflux for 3 hours. After cooling, the above reaction mixture was poured into ice (100%) and concentrated hydrochloric acid (
11'). Separated into each phase. The organic phase was washed with water, dried (Na2SQ) and evaporated in vacuo. 1-(3-trifluoromethylphenyl) is produced by fractional distillation of the residual oil.
12-methyl-12-propanol was produced. (b.p.
．． 63-64°C/1.0 side Hg, m. p. 55-56℃
Recrystallization from petroleum ether) Yield 73% (20.3 evenings).
The above substituted propanol (15.0 min, 0.069 mol) was mixed with dimethylaniline (9.32 min, 0.077 mol).
and dichloromethane (50%). The resulting solution was cooled and 2-bromopropionyl furomide (
On the evening of 22.2, 0.103 mol) was added dropwise over 1 hour. Hawk worship was continued overnight at room temperature. Water (200') was added to the above reaction mixture to separate the phases. After washing with sodium bicarbonate solution, the organic phase was evaporated in vacuo. The residual oil was diluted with ether (200) washed three times with 0.1N monosulfuric acid and water. The ether solution was dried (Na2S04) and evaporated in vacuo. From the residual fines, 2-promopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester (2.
10 days later, 87%) was obtained. The above bromoester (
0.059 mol) was dissolved in ethanol (600 mol) and cooled to 0°C.

This solution was saturated with ammonia (4 hours). Roping was continued for 5 hours at room temperature, during which time ammonia saturation was carried out twice more. The solvent was removed in vacuo and the residual oil was reduced to 0. was dissolved in hydrochloric acid and washed with ether. The acidic phase was made alkaline to pH 9.0 by addition of sodium hydroxide. Ether extraction of the alkaline phase was carried out twice and the organic layer was dried (Na2S04) and evaporated in vacuo. The hydrochloride salt was prepared from the basic oily residue. Recrystallization from acetone yielded 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propylester hydrochloride (m.p. 140-141°C, 12
．． 70 days, yield 66%) was obtained. Pharmacological method A
Biochemical test 1 Inhibition of absorption of 14C-5-HT and tritiated noradrenaline in vitro and in vivo The method described in European Journal of Pharmacology, 17 (1972), pp. 107-112 (Ross, Tested according to Ren et al. and 0 g.

Tricyclic antidepressants of the imibramine type added in vitro or administered in vivo to mice reduce the absorption of 14C-5-HT and 3H-NA in vitro. In in vitro experiments, different concentrations of test compounds were added to the incubation medium.
In the in vivo experiments, different doses of the test drug were administered intraperitoneally 30 minutes before the test animals were sacrificed. The incubation method was the same in the above two types of experiments, and each midbrain was removed and sliced.
14C-5-HTO.14C-5-HTO per 100 females in Kreps-Henseleit buffer (pH 7.4). 2
Nanomol, 3H-NAO. It was incubated in a mixture consisting of 2 nanomoles and 11 micromoles of glucose. Incubation time was 5 minutes. The radioactive amine absorbed into the brain slices was dissolved in toluene at 0.0%. Sollen-35, a solution of quaternary ammonium hydroxide
0 (Soluene-350: Trade name Packard)
The amount was determined by liquid scintillation according to the double labeling method. 50% reduction in active absorption (ED
The concentrations or doses resulting in 5o) were determined graphically from dose-response curves. Active absorption is defined as the portion of radioactive absorption that is suppressed by high concentrations of cocaine. All doses were administered to at least 4 test animals.
The results obtained in the above tests are listed in the table below. In the table, the code number CEA820 is 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propylester hydrochloride. means a compound according to the invention.

When this compound was administered intraperitoneally to mice, the LD value was 477 mmol/k9. Table Imipramine 0.1 0.06 2 4
61) 5-HT = 5-hydroxytryptamine 1 x 10-7 M2) NA = 1 noradrenaline 1 x
Evaluation of the Results Obtained in the 1017M Pharmacological Test The compounds of the invention block 5-hydroxytributamine absorption in brain slices in vitro and in vivo, but do not inhibit the absorption of noradrenaline.

These results indicate that the new compound is much more selective than imipramine in inhibiting the absorption of 5-hydroxytributamine.

Pharmaceutical composition The following examples illustrate the production of pharmaceutical compositions according to the invention.

The following composition was prepared for tablet production. a2
-Aminobrovanic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester hydrochloride (GEA820) 50 lactose
85 Yu potato powder
40 Polyvinylpyrrolidone 5
Tacellulose Avicel 18 Magnesium Tastearate 2# b 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester hydrochloride (GEA820) 100 Ta Lactose
90 Yu potato powder
50 Polyvinylpyrrolidone 5 Cellulose Avicel 23 Magnesium stearate Compositions of 2 or more a) and b
) were prepared from 100 hard tablets each containing 50 female and 9 of 100 active substances.

Claims (1)

[Claims] 1. A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R^0 is trifluoromethyl) and a pharmaceutically acceptable acid addition salt thereof. 2. The compound of item 1 above, wherein R^0 is trifluoromethyl present at the meta position of the phenyl ring, and a pharmaceutically acceptable acid addition salt thereof. 3. The compound of item 1 above, wherein R^0 is trifluoromethyl present at the para position of the phenyl ring, and a pharmaceutically acceptable acid addition salt thereof. 4. The compound according to any one of items 1 to 3 above in optically pure isomeric form. 5 Reacting a compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^0 is trifluoromethyl, and X is selected from halogen and p-toluenesulfonyloxy) with ammonia. A method for producing a compound of the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^0 represents the above meaning) and a pharmaceutically acceptable acid addition salt thereof, characterized by the following. 6. Mammals, including humans, containing a compound represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R^0 is trifluoromethyl) as an active ingredient together with a pharmaceutically acceptable carrier or diluent. Preparations for the treatment of depression.